Cyclic AMP‐induced loss of histone H3 phosphorylation and disruption of cell cycle progression mediated through a novel cAMP binding protein

Abstract

Cyclic AMP signaling is known to have a multitude of effects on cellular metabolism. It can be either inhibitory or stimulatory to cell growth depending on cell type. We have found that cAMP causes a rapid, significant loss of mitotic H3 phosphorylation at serines 10 and 28, and threonine 3. This loss is associated with cAMP-induced effects on cell cycle progression, including a delay in G2 and inhibition of mitotic entry. Interestingly, we have excluded the known cAMP binding proteins (protein kinase A, Epac, and cyclic nucleotide-gated ion channels) as mediators of this pathway through the use of specific inhibitors, antagonists, and agonists. We also excluded the possibility that a cAMP metabolite was the signaling molecule. We suggest that this may be a novel extracellular cAMP receptor because it responds efficiently to cAMP analogs with low lipophilicity and is activated by very low doses of membrane permeable cAMP derivatives. In fact, marked differences in analog lipophilicity do not correlate with significant changes in cellular response. Consistent with the idea that this may be an extracellular receptor, epinephrine induces rapid cAMP efflux from our cells. We conclude that cAMP signaling regulates cell cycle progression through a novel cyclic nucleotide binding protein. We are continuing with experiments to characterize and identify the receptor. Funding was provided by the National Cancer Institute in part through an Intramural Research Award to Dr. Catharine L. Smith.